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Pro-survival A1 is induced by pathogen ligands to limit myeloid cell death and NLRP3 inflammasome activation

ABSTRACT: Despite the importance of cell death in pathogen-induced innate immune responses, comparatively little is known about the regulation of intrinsic apoptosis during infection, nor how pathogens may subvert this pathway for their own benefit. Here, we identify that the pro-survival BCL-2 family member, A1, controls activation of the essential intrinsic apoptotic effectors, BAX/BAK, in macrophages and monocytes following bacterial lipopolysaccharide (LPS) sensing. We show that, due to its tight transcriptional and post-translational regulation, A1 acts as a molecular rheostat to regulate BAX/BAK-dependent apoptosis and the subsequent NLRP3 inflammasome-dependent and -independent maturation of pro-IL-1b. Furthermore, induction of A1 expression in inflammatory monocytes limits cell death modalities and IL-1b activation triggered by Neisseria gonorrhoeae-derived outer membrane vesicles (NOMVs). Consequently, A1-deficient mice exhibit heightened IL-1b production in response to NOMV injection. These findings reveal that bacteria can induce A1 expression to delay myeloid cell death and inflammatory responses, which has implications for the development of host-directed antimicrobial therapeutics.

ORGANISM(S): Mus musculus

PROVIDER: GSE214525 | GEO | 2023/10/17

REPOSITORIES: GEO

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